The therapeutic value of 17-keto steroids or 17-hydroxy steroids such as estrone and estradiol are well known. In addition to the steroids itself, also derivatives of estrone and estradiol have been found to have therapeutic value. In this respect especially 2-alkoxy-derivates of estrone and estradiol, such as 2-methoxy-estradiol, need to be mentioned.
2-methoxyestradiol, 1,3,5(10)-estratrien-2,3,17b-triol-2-methyl-ether (2-ME2) is an endogenous metabolite of estradiol. 2-ME2 has low estrogenic activity, but has been found to have important other biological effects, such as anti-cancer activity, as described herein below.
U.S. Pat. Nos. 5,504,074, 5,66,143 and 5,892,069 describe methods of treating mammalian diseases characterized by abnormal cell mitosis using 2-ME2. In addition WO-A-02/42319 describes 2-ME2 for the treatment of disease states characterized by abnormal angiogenesis.
Undesirable cell mitosis is characteristic of many diseases, including, but not limited to, cancer, atherosclerosis, proliferation of solid tumors, vascular malfunctions, endometriosis, retinopathies, arthropathies, and abnormal wound healing. In addition, cell mitosis is important in a wide variety of biological functions, including but not limited to the normal development of the embryo, formation of the corpus luteum, cyclic proliferation of uterine endometrium, wound healing and inflammatory and immune responses.
U.S. Pat. No. 5,521,168 describes the use of 2-ME2 for lowering intraocular pressure. 2-ME2 also inhibits estrogen-induced pituitary tumor angiogenesis and suppresses tumor growth in Fisher 344 rats as reported by Banerjee, S. K. et al., Proc. Amer. Assoc. Cancer Res. 39, March 1998.
Any therapeutic use of 2-ME2 in humans requires 2-ME2 having a high level of purity. In particular, since 2-ME2 has effects that are counteracted by estradiol and other estrogenic metabolites, it is desirable to have a 2-ME2 preparation substantially free of such contaminants. Effects that may be seen from contaminating estradiol, estrone and 2-hydroxtyestradiol include estrogenic effects such as feminization, endometrial proliferation, increased risk of uterine and breast cancer, developmental effects on sexual organs, inhibition of leucopoiesis and effects on haematopoietic cells. In addition, 4-hydroxyestradiol, 4-methoxyestradiol and estradiol are known to be at least suspected carcinogens.
These findings have prompted us to search for new synthetic procedures for the preparation of 2-alkoxy derivatives of estrone and estradiol such as 2-methoxyestradiol
Processes for the preparation of 2-ME2 are known in the art. For example, the article titled “Synthesis of 2-methoxyestrogens” by J. Fishman, published in the J. Am. Chem. Soc., 5 Mar. 1958, pages 1213-1216, describes the preparation of 2-methoxy-estradiol starting from estradiol. Also U.S. Pat. No. 6,051,726 describes the preparation of 2-alkoxyestradiols starting from estradiol. A disadvantage of such processes starting from estradiol, however, is the risk that the final product 2-ME2, will be contaminated with undesired estrogenically active compounds, such as the starting compound estradiol and/or any estrogenic intermediates. As explained above, such estrogenic impurities are highly undesirable.
EP-A-0776904 relates to the completely different technical field of the preparation of alkylketals of 3-keto-5(10),9(11)-gonadiene-derivatives. In its examples the preparation of such a gonadiene-derivative starting from estra-4,9-diene-3,17-dione is described. The estra-4,9-diene-3,17-dione compound is prepared by condensing (+)5α-hydroxy-7aβ-methyl-2,3,3aα,4,5,6,7,7a-octahydro-1H-inden-1-one-4α-(3-propionic acid)-lacton with 2-pentanone-neopentylacetale-5-magnesium chloride; oxidizing the 5α-hydroxy group; ring closure of the first ring (B); ketal cleavage; and ring closure of the second ring (A). EP-A-0776904 does not describe nor suggest the preparation of 2-substituted derivatives of estra-4,9-diene-3,17-dione.
Furthermore H. Ali et al, J. Chem. Soc. Perkin Trans. 1, 1991, page 2485-2491 describe the possibility of a route using 19-norsteroids with a suitable located double bond, followed by selective introduction of a functional group at position C2 or C4 and subsequent aromatization of the A-ring into 2- or 4-substituted-estradiol. No specific examples of such a 2-substitution according to this route were given.
Other preparations of 2-substituted estradiols are described in P. W. Le Quesne et al, Steroids, vol. 53/6, June 1989, page 649-661; L. R. Axelrod et al, Chem.&Ind., November 1959, page 1454-1455; and M. Mihailovic, Tetrahedron, vol. 33, 1977, page 235-237.